Mechano-energetic uncoupling in heart failure.

Dunja Aksentijevic, Simon Sedej, Jeremy Fauconnier, Melanie Paillard, Mahmoud Abdellatif, Katrin Streckfuss-Bömeke, Renée Ventura-Clapier, Jolanda van der Velden, Rudolf A de Boer, Edoardo Bertero, Jan Dudek, Vasco Sequeira, Christoph Maack

Journal: Nature reviews. Cardiology 2025;22(10):773-797

PMID: 40544170

Full Text on Nature Publishing Group View on PubMed

Abstract

Heart failure (HF) is a major global and life-threatening disease. Despite advances in therapies, the prevalence of HF is increasing owing to an ageing population and the pervasive pandemic of obesity and metabolic disorders, which have transformed the pathophysiology of HF. Changes in cardiac energy metabolism and the related energy deficit crucially contribute to the severity and type of HF. Furthermore, perturbations in excitation-contraction coupling, mitochondrial function and oxidative stress are characteristic features of HF. In this Review, we focus on the close interaction between cardiac mechanics and mitochondrial energetics, and decipher how this mechano-energetic coupling is disturbed in various acquired and hereditary forms of HF. In HF with reduced ejection fraction, defects in excitation-contraction coupling are key drivers of mechano-energetic uncoupling, whereas in HF with preserved ejection fraction, increased preload and afterload imposed by obesity, hypertension and age-dependent vascular stiffness increase mechanical workload, which is insufficiently matched by mitochondrial tricarboxylic acid cycle activity and ATP supply. In both scenarios, oxidative stress results from depletion of the antioxidative capacity and contributes to maladaptive cardiac remodelling and dysfunction. Several established and emerging treatments for HF target this mechano-energetic uncoupling, and a greater understanding of the underlying mechanisms will open new therapeutic opportunities to alleviate the burden of HF.

Address: William Harvey Research Institute, Bart's Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK. [email protected].; Department of Cardiology, Medical University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria.; Faculty of Medicine, University of Maribor, Maribor, Slovenia.; PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.; University Claude Bernard Lyon 1, CarMeN Laboratory-IRIS Team, INSERM INRAE, Bron, France.; Department of Cardiology, Medical University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria.; Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138 Institut Universitaire de France, Paris, France.; Institute of Pharmacology and Toxicology, Julius Maximilians University, Würzburg, Germany.; Medical Clinic I, Cardiology and Angiology, Justus Liebig University, Giessen, Germany.; Faculté de Pharmacie, Université Paris-Saclay, Bât Henri Moissan UMR-S 1180, Orsay, France.; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.; Erasmus Medical Center, CardioVascular Research Institute, Thorax Center, Department of Cardiology, Rotterdam, The Netherlands.; Cardiovascular Unit, Department of Internal Medicine, University of Genova, Genova, Italy.; Comprehensive Heart Failure Center Würzburg, Würzburg, Germany.; Comprehensive Heart Failure Center Würzburg, Würzburg, Germany. [email protected].; Medical Clinic 1, University Clinic Würzburg, Würzburg, Germany. [email protected].

DOI: 10.1038/s41569-025-01167-6

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https://doi.org/10.1038/s41569-025-01167-6

MeSH Terms: Humans, Heart Failure, Energy Metabolism, Oxidative Stress, Mitochondria, Heart, Excitation Contraction Coupling, Animals